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Enterovirus D68 infection induces IL-17–dependent neutrophilic airway inflammation and hyperresponsiveness
Charu Rajput, … , Emily T. Martin, Marc B. Hershenson
Charu Rajput, … , Emily T. Martin, Marc B. Hershenson
Published August 23, 2018
Citation Information: JCI Insight. 2018;3(16):e121882. https://doi.org/10.1172/jci.insight.121882.
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Research Article Infectious disease Pulmonology

Enterovirus D68 infection induces IL-17–dependent neutrophilic airway inflammation and hyperresponsiveness

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Abstract

Enterovirus D68 (EV-D68) shares biologic features with rhinovirus (RV). In 2014, a nationwide outbreak of EV-D68 was associated with severe asthma-like symptoms. We sought to develop a mouse model of EV-D68 infection and determine the mechanisms underlying airway disease. BALB/c mice were inoculated intranasally with EV-D68 (2014 isolate), RV-A1B, or sham, alone or in combination with anti–IL-17A or house dust mite (HDM) treatment. Like RV-A1B, lung EV-D68 viral RNA peaked 12 hours after infection. EV-D68 induced airway inflammation, expression of cytokines (TNF-α, IL-6, IL-12b, IL-17A, CXCL1, CXCL2, CXCL10, and CCL2), and airway hyperresponsiveness, which were suppressed by anti–IL-17A antibody. Neutrophilic inflammation and airway responsiveness were significantly higher after EV-D68 compared with RV-A1B infection. Flow cytometry showed increased lineage–, NKp46–, RORγt+ IL-17+ILC3s and γδ T cells in the lungs of EV-D68–treated mice compared with those in RV-treated mice. EV-D68 infection of HDM-exposed mice induced additive or synergistic increases in BAL neutrophils and eosinophils and expression of IL-17, CCL11, IL-5, and Muc5AC. Finally, patients from the 2014 epidemic period with EV-D68 showed significantly higher nasopharyngeal IL-17 mRNA levels compared with patients with RV-A infection. EV-D68 infection induces IL-17–dependent airway inflammation and hyperresponsiveness, which is greater than that generated by RV-A1B, consistent with the clinical picture of severe asthma-like symptoms.

Authors

Charu Rajput, Mingyuan Han, J. Kelley Bentley, Jing Lei, Tomoko Ishikawa, Qian Wu, Joanna L. Hinde, Amy P. Callear, Terri L. Stillwell, William T. Jackson, Emily T. Martin, Marc B. Hershenson

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Figure 6

EV-D68 induces type 2 cytokines, mucus genes, and greater airway hyperresponsiveness than RV-1B in allergen-challenged mice.

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EV-D68 induces type 2 cytokines, mucus genes, and greater airway hyperre...
Female 8- to 12-week-old BALB/c mice were challenged with house dust mite (HDM) and treated with sham, 5 × 106 ePFU of EV-D68, or 5 × 106 PFU of RV-A1B. Lungs were harvested, and RNA was extracted for qPCR. BAL analysis was also carried out in similarly treated mice. A separate set of mice was similarly treated and anesthetized and endotracheally intubated for measurement of airway responsiveness. (A) BAL cell counts for PBS/sham-, PBS/EV-D68–, HDM/sham-, and HDM/EV-D68–treated groups. (B) qPCR analysis of the indicated genes for the 4 groups. Data are shown as mean ± SEM of 3–4 mice/group for a single experiment; *P < 0.05 by ANOVA, compared with sham, †P < 0.05 by ANOVA, compared with PBS. (C) Airway methacholine responsiveness of the indicated treatment groups. n =3–4/group from a single experiment; *P < 0.05 by 2-way ANOVA, compared with sham; †P < 0.05 by 2-way ANOVA, compared with all other groups.

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